Dimethylformamide → 2-Chloro-6-(1-methyl-piperidin-4-yloxy)-pyridine

HRID 1822001Notes

Reaction equation

HRID 1822001 reaction equation
[H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[N:13]=1.CN(C=[O:23])C>>[NH3:7].[CH3:4][OH:3].[CH2:17]([O:23][C:4](=[O:3])[CH3:9])[CH3:12].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:3][CH:4]2[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]2)[N:13]=1

Participants

6

Reactant 4

HCID 6228Dimethylformamide2×HCID 169892,6-DichloropyridineHCID 24758Sodium hydrideHCID 660484-Piperidinol, 1-methyl-

Product 2

HCID 135639172-Chloro-6-(1-methyl-piperidin-4-yloxy)-pyridineYield 83%HCID 21873639Ethyl acetate methanol ammoniaYield 5%

Conditions

Temperature
0 °C

Procedure

Add sodium hydride (60% dispersion in mineral oil, 5.4 g, 135.1 mmol) to DMF (100 mL) and cool to 0° C. Add 4-hydroxy-1-methylpiperidine (15.6 g, 135.1 mmol) in DMF (100 mL). Warm the reaction to room temperature over 1 hr., add, in portions, 2,6-dichloropyridine (20.0 g, 135.1 mmol) as a solid. Stir the reaction and heat at 120° C. for 12 hr. Cool the reaction to room temperature and partition between diethyl ether and water. Extract 3 times with diethyl ether, combine organics and wash with saturated aqueous NaCl, dry over MgSO4, and concentrate. Chromatograph (silica gel, eluting with ethylacetate, then 5% 2 M NH3-methanol/ethylacetate), to provide the title compound as a pale yellow liquid (25.5 g, 83% yield). Mass spectrum (ion spray): m/z=227.1 (M+1); 1H NMR: δ (CDCl3, ppm) 7.46 (t, J=7.2 Hz, 15.6 Hz, 1H), 6.82 (d, J=6.3 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 5.03 (m, 1H), 2.66 (bs, 2H), 2.28 (bs, 5H), 2.00 (m, 2H), 1.80 (m, 2H); Anal calcd for C11H15ClN2O.0.8H2O: Theory: C, 54.80; H, 6.94; N, 11.62. Found: C, 54.51; H, 6.20; N, 11.60.

Workup

  1. temperatureWarm
  2. customthe reaction to room temperature over 1 hr
  3. customthe reaction
  4. temperatureheat at 120° C. for 12 hr
  5. temperatureCool
  6. customthe reaction to room temperature
  7. custompartition between diethyl ether and water
  8. extractionExtract 3 times with diethyl ether
  9. washwash with saturated aqueous NaCl
  10. dry with materialdry over MgSO4
  11. concentrationconcentrate
  12. washChromatograph (silica gel, eluting with ethylacetate

Sources & evidence

ORD record
ord-a51e993be16640e7bb22532740ebac34
Source dataset
uspto-grants-2009_10
Patent number
US07608629B2

Reaction notes

Loading…